mTOR: taking cues from the immune microenvironment

Abstract

The ultimate outcome of T cell receptor recognition is determined by the context in which the antigen is encountered. In this fashion both antigen-presenting cells and T cells must integrate multiple environmental cues in the form of pathogen-associated molecular patterns, cytokines and accessory molecule signals. The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental signals critical to regulating metabolism and cell survival. In this paper we review the data demonstrating that mTOR integrates signals from the immune microenvironment and therefore facilitates the generation of the adaptive immune response. Specifically, we review the role of mTOR in promoting dendritic cell activation and maturation, in regulating full T cell activation versus anergy, and influencing the induction of regulatory T cells.

Figure 1

Schematic of mammalian target of rapamycin (mTOR) signalling in T cells. Environmental cues including costimulatory molecule engagement (CD28), growth factors [for example, interleukin-2 (IL-2)], amino acids, and insulin stimulate the activity of the phosphatidylinositol 3-kinase (PI3K) signalling cascade, promoting the partial activation of Akt on threonine 308, upstream of mTOR. The mTOR signalling proceeds via two complexes, TORC1 (characterized by mTOR and raptor) and TORC2 (characterized by mTOR and rictor). While TORC1 is activated in part by the inhibition of TSC2, a biochemical inhibitor of TORC1, the precise upstream events leading to TORC2 activation remain unclear. TORC1 phosphorylates (among many substrates) the ribosomal S6K1 and the translational repressor 4E-BP1. TORC2 phosphorylates Akt on serine 473, locking it into a fully activated conformation. Rapamycin interferes with TORC1 signalling by interfering with mTOR–raptor interactions. Rapamycin can also inhibit TORC2 signalling, although the mechanism is not entirely clear.

Figure 2

Environmental signals (Danger) leading to the activation of mammalian target of rapamycin (mTOR) can induce the activation and maturation of immature DCs. This activation leads to the up-regulation of B7 molecules and the production of type I interferons. In mature myeloid dendritic cells (mDCs) and monocyte-derived lineages, persistent Toll-like receptor (TLR) stimulation may stimulate mTOR to induce a negative feedback loop, leading to the inhibition of pro-inflammatory cytokine secretion. Naïve T cells receiving stimulation in the context of mTOR activation differentiate into effector cells, while those receiving T cell receptor stimulation with decreased mTOR activation (or rapamycin treatment) default into regulatory T cells. Furthermore, differentiated effector cells receiving stimulation with full mTOR activation become fully activated, while those receiving suboptimal mTOR activation are rendered anergic.